Project Summary/Abstract The main objectives of the Metals in the Trial to Assess Chelation Therapy 2 (TACT2M) are to evaluate whether long-term edetate disodium (EDTA)-based chelation infusions can significantly reduce body lead and cadmium levels and to determine whether this effect explains the reduction in major cardiovascular events caused by EDTA chelation therapy. TACT2M is a companion study to TACT2 and will be integrated into the clinical trial platform of TACT2, which will enroll 1200 post-MI patients with diabetes who are at least 50 years old and have a creatinine of 2.0 mg/dL or less. TACT2, a replication study of TACT (referred to as TACT1), will be a 2X2 factorial trial, randomizing patients to 4 groups, defined by both active vs placebo infusions and active vs placebo oral multivitamins and multiminerals (OMVM). NCCIH has funded the UG3 1-year Planning Phase of TACT2. The co-primary endpoints of TACT2M are: 1] the change in blood lead level from baseline to infusion 40 or 1 year, whichever is first, and 2] the change in urine cadmium controlled for creatinine (Cd mcg/ gram creatinine) from baseline to infusion 40 or 1 year, whichever is first. TACT2M has 3 Specific Aims: 1] Compare the change in metal internal dose (blood lead and urine cadmium) in TACT2 participants, from baseline to infusion 40 or 1 year in the active infusion arm; 2] Evaluate whether higher baseline metal internal dose (blood lead and urine cadmium) and the extent of depletion of those stores identifies patients more likely to show benefit from chelation; 3] Collect a biorepository of specimens to support future mechanistic work. Samples of whole blood and urine will be stored at -80C in a secured biorepository to ensure their availability for the evaluation of future hypotheses that will be guided by the results of the trial. Moreover, TACT2M represents a unique opportunity to assess the following Exploratory Aims: a] whether post- infusion urine measurements, alone and in comparison to the corresponding pre-infusion measurements, have clinical significance; b] whether OMVM interact with edetate disodium-mediated metal excretion; and c] whether the suite of additional toxic and essential metals measured in blood and urine by the ICPMS analytic technique used by the metals lab, many of which are not chelated by edetate disodium, have clinical significance in preliminary testing. In summary, TACT2M will assess whether metal chelation is a possible mechanism for improved clinical outcomes in post-MI diabetic patients receiving edetate disodium chelation. The integration of TACT2M into the existing TACT2 study is an efficient method to inform the treatment of patients with a history of MI and diabetes.